Benzylic Position Research Articles

Electrochemical Benzylic C-H Functionalization with Isocyanides.

We report the challenging direct carbamoylation or cyanation of benzylic C(sp3)-H bonds with an isocyanide via an electrochemical process giving rise to structures that are encountered in several biologically relevant compounds and drugs. This transformation proceeds under mild conditions without the need for any external oxidant and avoids the necessity to start from a prefunctionalized benzylic substrate or the deployment of the cation pool method. The anodic oxidation of the benzylic position and the subsequent addition of the isocyanide lead to the formation of a C-C bond and to a nitrilium cation that hydrolyzes to yield α-aryl acetamide derivatives, whereas the elimination of a t-butyl cation delivers α-aryl acetonitrile derivatives.

Photoenolization/nucleophilic addition enables direct access to 3-alkyl-3-hydroxy-indolin-2-ones

A light-driven, catalyst- and additive-free photoenolization/nucleophilic addition reaction for the synthesis of 3-benzyl-3-hydroxyindolin-2-ones is presented. In this reaction, 2-methylbenzophenones undergo light-induced enolization process to afford hydroxy-o-quinodimethanes (hydroxy-o-QDMs), which are then immediately captured by the electrophilic isatins. The reaction utilizes green and clean light energy to realize the C–H activation of the inert benzyl position of 2-methylbenzophenones. This method tolerates a wide scope of substrates and provides concise access to a series of novel 3-benzyl-3-hydroxyindolin-2-ones with 60–99% yields.

Synthesis of Aryloxiranes and Arylcyclopropanes via Deprotonation of Benzyl Chlorides

AbstractUpon the action of strong bases at low temperature, benzyl chloride and its ring-substituted derivatives undergo deprotonation at the benzylic position and the produced carbanions react with aldehydes, ketones and Michael acceptors to form aryl oxiranes and cyclopropanes.

NMR and MD Analysis of the Bonding Interaction of Vancomycin with Muramyl Pentapeptide.

The article describes an NMR spectroscopy study of interactions between vancomycin and a muramyl pentapeptide in two complexes: vancomycin and a native muramyl pentapeptide ended with D-alanine (MPP-D-Ala), and vancomycin and a modified muramyl pentapeptide ended with D-serine (MPP-D-Ser). The measurements were made in a 9:1 mixture of H2O and D2O. The obtained results confirmed the presence of hydrogen bonds previously described in the literature. At the same time, thanks to the pentapeptide model used, we were able to prove the presence of two more hydrogen bonds formed by the side chain amino group of L-lysine and oxygen atoms from the vancomycin carboxyl and amide groups. This type of interaction has not been described before. The existence of these hydrogen bonds was confirmed by the 1H NMR and molecular modeling. The formation of these bonds incurs additional through-space interactions, visible in the NOESY spectrum, between the protons of the L-lysine amino group and a vancomycin-facing hydrogen atom in the benzylic position. The presence of such interactions was also confirmed by molecular dynamics trajectory analysis.

1,3-Oxyalkynylation of Aryl Cyclopropanes with Ethylnylbenziodoxolones Using Photoredox Catalysis.

Alkynes and cyclopropanes are vital motifs in chemistry. Herein, a photoredox catalyzed 1,3-oxyalkynylation of aryl cyclopropanes with ethylnylbenziodoxolones (EBXs) in an atom-economic fashion is described. This cascade comprises single-electron oxidation of the aryl cyclopropane and nucleophilic ring opening followed by radical alkynylation at the benzylic position. The EBX compounds act as bifunctional reagents providing the nucleophilic acid as well as the alkynyl entity. The introduced method features mild conditions and wide substrate scope.

Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol O -Nucleophiles

Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol <i>O</i> -Nucleophiles

Photoinduced rearrangement of α-(2-nitrophenyl)ketones.

Photoirradiation of α-(2-nitrophenyl)ketones produced cyclic hydroxamates. The reaction proceeded via photoinduced oxygen transfer from the nitro group to the benzylic position, forming an α-hydroxyketone having a nitroso group. Subsequent addition of the nitroso group to the ketone moiety and the concomitant cleavage of the C-C σ bond between the carbonyl group and the benzyl position produced hydroxamic acid, which underwent formation of a hemiacetal to give cyclic hydroxamate.

A class of electron-deficient units: fluorenone imide and its electron-withdrawing group-functionalized derivatives.

This study describes the development of a series of strong electron-deficient acceptor units, namely, fluorenone imide (FOI) and its derivatives, functionalized with various electron-withdrawing groups, which are developed via functionalization of the fluorenone unit with an imide group and then systematic variation of the attached electron-withdrawing groups at the bridgehead benzylic position.

Vinylogous and Arylogous Stereoselective Base-Promoted Phase-Transfer Catalysis

Vinylogous enolate and enolate-type carbanions, generated by deprotonation of α,β-unsaturated compounds and characterized by delocalization of the negative charge over two or more carbon atoms, are extensively used in organic synthesis, enabling functionalization and C–C bond formation at remote positions. Similarly, reactions with electrophiles at benzylic and heterobenzylic position are performed through generation of arylogous and heteroarylogous enolate-type nucleophiles. Although widely exploited in metal-catalysis and organocatalysis, it is only in recent years that the vinylogy and arylogy principles have been translated fruitfully in phase-transfer catalyzed processes. This review provides an overview of the methods developed to date, involving vinylogous and (hetero)arylogous carbon nucleophiles under phase-transfer catalytic conditions, highlighting main mechanistic aspects.

Electrochemical oxidation-induced benzyl C[sbnd]H carbonylation for the synthesis of aromatic α-diketones

Electrochemical oxidation-induced direct carbonylation of benzyl CH bond for the synthesis of aromatic α-diketones is described. In this process, tetrabutylammonium iodide (nBu4NI) not only acts as an electrolyte, but its iodine anion is oxidized to an iodine radical at the anode, acting as a hydrogen atom transfer agent. The iodine radical extracts the benzyl hydrogen atom and causes the carbonylation of the benzyl position, where O2 in the air is used as an oxygen source.

Photoionization of buckybowls: Sumanene and derivatives

The electronic structures of sumanene and several heterasumanenes have been calculated using high-level ab initio method: Green’s function method (OVGF). The vertical, valence ionization energies were calculated and gas phase photoelectron spectra simulated on the basis of those ionization energies. The Franck-Condon analysis of vibronic effects has also been performed and changes between molecular geometries in neutral and ionic state have been discussed Standard formation enthalpies for some sumanenes were calculated using isodesmic reaction scheme. The results help in the understanding of how is the electronic structure affected when molecule deviates from planar geometry and what is the influence of substituents in benzylic positions. We have demonstrated that the substituent effects affect not only geometry, but also the electronic structure (reflected in ionization energies). This can be used in preparing new functional materials for various applications.

Back Cover: Palladium Nanoparticles for the Deuteration and Tritiation of Benzylic Positions on Complex Molecules (Angew. Chem. Int. Ed. 51/2021)

Palladium nanoparticles catalyze the deuteration and tritiation of benzylic positions on complex molecules, as reported by Viktor Pfeifer et al. in their Research Article on page 26671. In the picture, yellow diatomic molecules symbolize D2 or T2 gas, while the unlabeled molecular structures of celecoxib and UCB-J on the left and the identical labeled structures on the right with shining benzylic positions are shown to illustrate the hydrogen isotope exchange reaction.

Palladium Nanoparticles for the Deuteration and Tritiation of Benzylic Positions on Complex Molecules

AbstractPalladium nanoparticles (PdNp) were revealed as an efficient hydrogen isotope exchange catalyst for the deuterium and tritium labeling of benzylic positions of complex molecules. A practical way to obtain small palladium nanoparticles and to apply them as a catalyst for hydrogen isotope exchange (HIE) is presented. Several model compounds and popular bioactive molecules were submitted to HIE reactions catalyzed by the PdNp. Benzylic positions situated far away from heteroatoms were labeled with high isotopic enrichments. The observed non‐directed HIE gave rise to regioselectivities complementary to those obtained with other methods, which typically require specific directing groups. For this reason, the successful deuteration of a broad variety of benzylic positions created a helpful tool to produce internal LC‐MS standards of complex drugs. Furthermore, this nanocatalyst paved the way for the radiolabeling of drug molecules with high specific activities by using low pressures of tritium gas.

Alkylation of monomeric, dimeric, and polymeric lignin models through carbon-hydrogen activation using Ru-catalyzed Murai reaction

In this study, we have assessed directed carbon-hydrogen activation (CHA) for alkylation of monomeric, dimeric, and polymeric lignin models using Murai's catalyst [RuH2(CO)(PPh3)3]. Based on related work from our laboratory showing that isolated organosolv lignin bears benzylic directing groups ideal for CHA reactions, this approach could offer new methodology for the valorization of biorefinery lignin. Monomeric and dimeric models bearing a keto group at the benzylic position undergo Ru-catalyzed alkylation in good to excellent yield. Similarly, models bearing a benzylic OH group also undergo alkylation via a tandem oxidation/alkylation process enabled by the Ru catalyst. Polymeric models show low levels of functionalization as a result of the poor solubility of the starting polymer. With unsymmetrical models, functionalization occurs first at the least sterically hindered ortho-site, but a subsequent alkylation, leading to disubstituted products can occur at the more sterically hindered site, leading to hexasubstituted arenes. The reaction shows sensitivity to free phenolic OH groups, which appears to reduce the yield in some reactions, and is also a contributing factor to the low yields observed with polymeric lignin models. Combining CHA methodology with lignin isolation technology able to introduce appropriate directing groups for catalytic functionalization will form the basis for improved conversion of lignin to high value chemical products.

Palladium Nanoparticles for the Deuteration and Tritiation of Benzylic Positions on Complex Molecules

Palladium nanoparticles (PdNp) were revealed as an efficient hydrogen isotope exchange catalyst for the deuterium and tritium labeling of benzylic positions of complex molecules. A practical way to obtain small palladium nanoparticles and to apply them as a catalyst for hydrogen isotope exchange (HIE) is presented. Several model compounds and popular bioactive molecules were submitted to HIE reactions catalyzed by the PdNp. Benzylic positions situated far away from heteroatoms were labeled with high isotopic enrichments. The observed non-directed HIE gave rise to regioselectivities complementary to those obtained with other methods, which typically require specific directing groups. For this reason, the successful deuteration of a broad variety of benzylic positions created a helpful tool to produce internal LC-MS standards of complex drugs. Furthermore, this nanocatalyst paved the way for the radiolabeling of drug molecules with high specific activities by using low pressures of tritium gas.

A Bioreductive Protecting Group for RNA Synthesis

This protocol describes a method for the preparation of ribonucleoside phosphoramidite bearing a bioreductive protecting group on the 2'-OH group and its application in the synthesis of bioreduction-responsive oligonucleotides. The protecting group used in this method consists of the modified 4-nitrobenzyl skeleton, which has gem-dimethyl groups at benzylic positions to enable deprotection under physiological conditions. Applying the synthesized ribonucleoside phosphoramidite to solid-phase synthesis of oligonucleotides, a 2'-O-protected oligonucleotide was obtained without any undesirable cleavages under standard oligonucleotide synthesis conditions. The 2'-O-protected oligonucleotide was then treated with a combination of nitroreductase (Escherichia coli) and NADH as a bioreduction system for cleavage of the 2'-O-protecting group. After reduction of the nitro group, the protecting group was deprotected in a time-dependent manner. Thus, this protection technology is a potential new tool for production of reduction-responsive RNA-based materials that can be used in life and medical sciences. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of ribonucleoside phosphoramidite bearing a bioreductive protecting group Basic Protocol 2: Synthesis of 2'-O-protected oligonucleotides and their deprotection properties under bioreduction.

Ruthenium(II)-Catalyzed Regioselective C-H Olefination of Aromatic Ketones and Amides with Allyl Sulfones.

A Ru(II)-catalyzed cross-dehydrogenative Heck-type olefination of arenes with allyl sulfones leveraging the assistance of weakly coordinating ketone and amide functional groups is reported. It features a distinct reactivity profile in comparison to other allylic congeners, where β-sulfonyl elimination was not detected. The ambiphilic nature of the allyl sulfone side chain has also been demonstrated through intramolecular aza-Michael addition and aldol condensation. Mechanistic studies indicated the involvement of a reversible metalation step, where β-hydride elimination takes place selectively from the benzylic position.

Practical One-Pot Multistep Synthesis of 2H-1,3-Benzoxazines Using Copper, Hydrogen Peroxide and Triethylamine.

In this article, we describe simple one-pot syntheses of 2H-1,3-benzoxazines from ketones utilizing an imino-pyridine directing group (R1R2-C=N-CH2-Pyr), which promotes a Cu-directed sp2 hydroxylation using H2O2 as oxidant and followed by an oxidative intramolecular C-O bond formation upon addition of NEt3. This synthetic protocol is utilized in the gram scale synthesis of the 2H-1,3-benzoxazine derived from benzophenone. Mechanistic studies reveal that the cyclization occurs via deprotonation of the benzylic position of the directing group to produce a 2-azallyl anion intermediate, which is oxidized to the corresponding 2-azaallyl radical before the C-O bond formation event. Understanding of the cyclization mechanism also allowed us to develop reaction conditions that utilize catalytic amounts of Cu.

Role of Benzylic Deprotonation in Nickel-Catalyzed Benzylic Dehydrogenation

AbstractAlkylarenes are readily functionalized via the corresponding benzylic anions. Benzylic anions have been used for a range of catalytic reactions, including Ni-catalyzed dehydrogenation. Interestingly, the employment of Zn(TMP)2 for slow and incomplete deprotonation of the benzylic position was observed. This manuscript describes a preliminary investigation into the deprotonation of heteroarenes and its relationship to Ni-catalyzed benzylic dehydrogenation.

A Highly Congested Dioxapyrenophane from an Attempted Synthesis of the Highly‐Strained 1,1,6,6‐Tetramethyl[6](2,11)teropyrenophane

AbstractSynthetic studies aimed at the synthesis of 1,1,6,6‐tetramethyl[6](2,11)teropyrenophane (3 a) led to the synthesis of the structurally unusual dioxa[6.3.3](7,1,3)pyrenophane 29. The strategic approach to access 3 a resembled the one that was successfully applied in the synthesis of the higher homologues 3 b‐e, but had a key difference: three‐atom bridges were utilized instead of two‐atom bridges in the construction of the intermediate pyrenophanes which were slated to serve as precursors to access 3 a. After stepwise approaches to construct the bridges failed, it was found that two ether bridges could be installed easily in the same reaction to afford dioxa[6.3.3](7,1,3)pyrenophane 29. Considerable steric congestion around the dioxa[3.3]metacyclophane substructure arises from the presence of a methyl group on each of the benzylic positions of the three‐atom bridges. Although the conversion of 29 into a [6](2,11)teropyrenophane was unsuccessful, the finding that ether bridges in this structurally uncommon dioxacyclophane could be formed easily offers new opportunities for the synthesis of related cyclophanes that may ultimately serve as viable precursors for the synthesis of [n](2,11)teropyrenophanes.